Abstract Annual epidemics of influenza cause substantial morbidity in the US with up to 40,000 deaths/year and many hospitalizations, emergency department visits, outpatient visits, and costs. The Advisory Committee on Immunization Practices (ACIP) recommends annual influenza vaccination for all people above 6 months of age. However, less than half of all Americans receive the influenza vaccine. Two sets of interventions that can improve influenza vaccination rates include patient reminders (generally by mail or phone), and enhancing access and ease of obtaining the vaccine. However, due to resource limitations and difficulty scaling up reminders, only a small proportion of practices or health systems remind patients about the need for vaccination, and few systems implement innovative strategies to ease access to influenza vaccination. A technological breakthrough that might overcome these barriers is the electronic health records patient portal. Patient portals are secure, web-based communication systems, embedded within electronic health records (EHRs), allowing patients and providers to communicate via email and the internet. Portal-based reminder has the potential to raise vaccination rates for several reasons: the messages come from the patient's provider, portal reminders are easily scalable, portal messages can be personalized by drawing on information found in the patient's medical record, and portals can facilitate access by helping patients schedule their own appointments for vaccination. This study will implement and evaluate a portal reminder system for influenza vaccination across a large UCLA-wide health system that serves >275,000 patients in 49 primary care practices, half of whom use the portal. For Aim 1 we will adapt algorithms, educational messages, and protocols previously used for mailed or phone influenza vaccine reminder/recall to create a patient portal research platform. For Aim 2, we will assess the impact of portal reminders, and key design features of these reminders, on influenza vaccination rates and costs using 3 sequential RCTs over 3 flu seasons. RCT #1 will test the optimal number of portal reminders (3, 2, or 1 vs. 0). RCT #2 will test the additional benefit of adding patient direct appointment scheduling to the portal reminder system. RCT #3 will test the additional benefit of linking portal reminders with the EHR to customize portal messages. For Aim 3 we will develop an adoption guide/toolkit for use by other health systems. We will disseminate the portal reminder system in a network of Los Angeles Department Health community health centers serving more than 30,000 low-income patients. By study end we will have an advanced influenza vaccine portal reminder system, ready for dissemination.